Cotinine has been synthesized by reacting bromine with nicotine to form an intermediate, dibromocotinine hydrobromide perbromide, which is then reduced by the addition of zinc and hydrochloric acid to yield cotinine (Biochemical Preparations, Vol. 10, pp. 36-39). Japanese patent JP51105076A dated Sep. 17, 1976 describes another method wherein nicotine is reacted with hydrobromic acid and hydrogen peroxide to produce the intermediate which is reduced and debrominated by the usual method without isolation. In another method, cotinine was produced by oxidizing nicotine with a Hg(II)-EDTA complex (Synthetic Communications, 18(12), pp. 1331-1337; 1988). A major object of the present invention is to avoid the use of toxic substances such as bromine, mercury and to avoid the combined use of hydrobromic acid and hydrogen peroxide as described in JP 51105076A because of the expense of HBr and because the yield of cotinine was found by us to be relatively poor. The use of toxic materials is particularly objectionable where the final product is to be formed without physical separation from the intermediate. In addition, safety problems are incurred and manufacturing costs are increased because of the special handling and treatment required for the toxic substances previously required.
Accordingly, it is a major object of the present invention to provide an improved commercial method for producing cotinine in high yields and on a commercial scale without the drawback produced by the toxicity problems, poor yields, and costly reagents needed in previous methods.
These and other more detailed and specific objects of the present invention will be better understood by reference to the following figures and detailed description which illustrate by way of example but a few of the various forms of the invention within the scope of the appended claims.